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18f-saccharide-folates

Active Publication Date: 2014-07-10
MERCK & CIE KG
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The present invention provides compounds and pharmaceutical compositions that can be used for diagnostic imaging or monitoring of radiotherapy in mammals, such as animals or humans. These compounds can be easily prepared using the components provided in a kit, and can be injected or administered in various ways for effective imaging or therapy. The technical effects of this invention include improved diagnosis and treatment of cancer and other diseases using convenient and safe methods.

Problems solved by technology

However SPECT provides less sensitivity than PET and beside a few approaches quantification methods are lacking.
Yet, many methodologies still suffer from drawbacks including time-consuming radiosyntheses giving low radiochemical yields, or unfavorable pharmacokinetics for molecular imaging purposes, and the like.

Method used

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Examples

Experimental program
Comparison scheme
Effect test

example 1

Synthesis of γ-Folate Alkyne Precursor (According to FIG. 1A)

(a) Synthesis of (S)-methyl 2-((S)-4-((tert-butoxycarbonyl)-amino)-5-methoxy-5-oxopentananamido)pent-4-ynoate (step a)

[0271]Commercial available BocGluOMe (402 mg, 1.54 mmol) was dissolved in dry DMF (4 mL) and Et3N (428 μL, 2 eq.) was added. HBTU (700 mg, 1.85 mmol) was added at 0° C. and the mixture was stirred for half an hour. The solution of the activated acid was transferred to a solution of H-Pra-OMe.HCl (205 mg, 1.62 mmol) in dry DMF (4 mL) containing Et3N (856 μL, 4 eq.) at 0° C. The mixture was stirred for 1 h at 0° C., warmed to rt and stirred over night. The product was extracted with citric acid (1 M) and ethyl acetate. The organic phase was rinsed with brine, dried over Na2SO4 and concentrated under reduced pressure. Purification was achieved by flash chromatography on silicagel with CH2Cl2 / MeOH (50:1) provided the product as a white solid (467 mg, 82%). 1H-NMR (DMSO-d6) δ / ppm 8.40 (d, 1H, J=7.3 Hz), 7.27 (d,...

example 2

Synthesis of γ-[19F]-Glucose Folate Reference (According to FIG. 2A)

[0276]The synthesis of 2-deoxy-2-fluoroglucopyranosyl azide was prepared according to the procedure according the literature procedure (e.g. Maschauer and Prante, Carbohydr. Res. 2009).

[0277]γ-Folate alkyne (10 mg, 19 μmol) was dissolved in tert-BuOH / H2O (1:1, 1 mL) in an Eppendorf tube and 2-deoxy-2-fluoroglucopyranosyl azide (11.6 mg, 56 μmol), 0.1 M Cu(OAc)2 solution (0.1 eq., 19 μL) and 0.1 M sodium ascorbate solution (0.2 eq., 38 μL) were added. The solution was shaken at rt and 500 rpm for 1 h until complete conversion (analysis via HPLC). For isolation of the product, the mixture was submitted to semi-preparative HPLC. The desired fraction was collected and lyophilized to provide the product as a yellow powder (7.2 mg, 52%, purity according to HPLC>98%). 1H-NMR (D2O / NaOD) δ / ppm 8.74 (s, 1H), 7.98 (s, 1H), 7.61 (d, 2H, J=8.8 Hz), 6.76 (d, 2H, J=8.8 Hz), 5.89 (dd, 1H, J1=2.6 Hz, J2=9.0 Hz), 4.91 (t, 1H, J=9.0 H...

example 3

Synthesis of γ-[18F]-glucose folate (according to FIG. 2A)

[0278]The 3,4,6-tri-O-acetyl-2-O-trifluoromethanesulfonyl-β-D-mannopyranosyl azide precursor used for coupling the 18F-substituted glucose via click reaction to the folate, was obtained according to literature procedures (e.g. Maschauer and Prante, Carbohydr. Res. 2009, 753; Takatani et al Carbohydr. Res. 2003, 1073).

(b) Radiosynthesis of 2-[18F]fluoroglucopyranosyl azide

[0279]To the dry 18F-fluoride-cryptate complex the precursor, 3,4,6-tri-O-acetyl-2-O-trifluoromethanesulfonyl-β-D-mannopyranosyl azide (3.0 mg, 6.5 μmol), in 0.30 mL of anhydrous acetonitrile was added. The mixture was stirred for 5 min at 80° C. to afford a 18F-incorporation of maximum 75% according to radio-UPLC analysis. After 5 min of cooling and addition of 8 mL of water, the mixture was passed through a reversed-phase cartridge (Sep-Pak C18 Plus; Waters; preconditioned with MeOH and H2O). The cartridge was washed with 5 mL of water. The 18F-labelled pro...

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Abstract

The present invention is directed towards new 18F-folate radiopharmaceuticals, wherein the 18F isotope is linked via a prosthetic group, more specifically via a prosthetic group having a saccharide group, such as a cyclic mono- or oligosaccharide, preferably based on a pyranoside or furanoside, which is covalently linked to the glutamate portion of a folate or derivative thereof, a method of their preparation, as well as their use in diagnosis and monitoring of cancer and inflammatory and autoimmune diseases and therapy thereof.

Description

FIELD OF INVENTION[0001]The present invention is directed towards new 18F-folate radiopharmaceuticals, wherein the 18F isotope is linked via a prosthetic group, more specifically via a prosthetic group comprising a saccharide group, such as cyclic mono- and oligosaccharides, which is covalently linked to the glutamate portion of a folate or derivative thereof, a method of their preparation, as well as their use in diagnosis and monitoring of cancer and inflammatory and autoimmune diseases and therapy thereof.BACKGROUND[0002]Cell-specific targeting for delivery of effector moieties such as diagnostic or therapeutic agents is a widely researched field and has led to the development of non-invasive diagnostic and / or therapeutic medical applications. In particular in the field of nuclear medicine procedures and treatments, which employ radioactive materials emitting electromagnetic radiations as γ-rays or photons or particle emitting radiation, selective localization of these radioactiv...

Claims

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Application Information

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IPC IPC(8): A61K51/04G01N33/60
CPCG01N33/60A61K51/0491C07B59/005Y02P20/55
Inventor SCHIBLI, ROGERMOSER, RUDOLFMULLER, CRISTINA MAGDALENAAMETAMEY, SIMON MENSAHFISCHER, CINDY RAMONAGROEHN, VIOLA
Owner MERCK & CIE KG
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